PROJECT SUMMARY The first synapse in the visual system, between the photoreceptors and bipolar cells, includes lateral inhibition from horizontal cells, that enhances the contrast of the neural representation. A central goal for this project will be to adapt a recently developed horizontal slice method to the primate retina, which will facilitate making paired electrophysiological recordings between cone photoreceptors and horizontal cells in healthy, light-responsive tissue. The new preparation will enable us to address two fundamental outstanding questions regarding the nature of the lateral inhibition produced by the horizontal cells. The first aim will investigate the two main hypotheses that have been proposed to account for horizontal cell feedback to cone photoreceptors ? the pH hypothesis and the ephaptic hypothesis. Paired recordings between cones and horizontal cells will be used to test specific predictions, and determine which mechanism is applicable in the mammalian retina. The second aim will investigate a second unresolved question regarding lateral inhibition; whether horizontal cells make feed-forward GABAergic inhibitory connections with bipolar cell dendrites. Paired recordings between horizontal cells and bipolar cells will be made to directly test for the presence of conventional GABAergic synapses. The results obtained in the primate will be directly applicable to questions related to human visual health and disease, and are in accord with the National Eye Institute?s goals to improve understanding of neural circuits in the retina for the purposes of informing efforts to develop diagnostic tools and therapies for disease.